Use of substituted aminomethyl chromans

ABSTRACT

Compounds of formula I in which R has a meaning as indicated in claim  1 , or one of their optical isomers or pharmaceutically acceptable salts, used for the treatment of extrapyramidal movement disorders and/or adverse effects in extrapyramidal movement disorders and/or for the treatment of extrapyramidal symptoms (EPS) induced by neuroleptics.

The present invention relates to the novel use of substitutedaminomethyl chromans for the treatment of movement disorders and ofadverse effects induced by drugs administered to treat extrapyramidalmovement disorders.

The invention preferably relates to the use of substituted aminomethylchromans of formula I

in which

R represents hydrogen or a hydroxyl protecting group,

and their optical isomers and pharmaceutically acceptable salts orsolvates, in particular2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-7-ol,2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-8-olor an optical isomer or physiologically acceptable salts or solvatesthereof, for the manufacture of a medicament for the treatment ofextrapyramidal movement disorders and/or for the manufacture of amedicament for the treatment of adverse effects of anti-Parkinsoniandrugs in extrapyramidal movement disorders and/or for the manufacture ofa medicament for the treatment of extrapyramidal symptoms (EPS) inducedby neuroleptics. The compounds of Formula I are especially useful in thetreatment of dyskinesia.

U.S. Pat. No. 5,767,132 describe similar aminomethyl chroman derivativeswhich are suitable for prophylaxis and control of the sequelae ofcerebral infarction (apoplexia cerebri) such as stroke and cerebralischaemia, for prophylaxis and control of cerebral disorders, e.g.migraine, especially in geriatrics in a manner similar to certain ergotalkaloids, the treatment of anxiety, tension and depression states,sexual dysfunctions caused by the central nervous system, fordisturbances in sleep or absorption of food or for the treatment ofpsychosis (schizophrenia).

Additionally, they are suitable to eliminate cognitive deficiencies, toimprove powers of learning and memory and to treat Alzheimer's disease.They can be furthermore used for treating side-effects in the treatmentof hypertension, in endocrinology and gynecology, e.g. for the treatmentof acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndromeor undesired puerperal lactation.

Similar compounds are described in Drug Metabolism and Disposition, Vol.29, No. 7, 1042-1050, 2001.

In contrast to the compounds disclosed in U.S. Pat. No. 5,767,132, thecompounds according to formula I are merely agonists of the 5-HT_(1A)receptor and antagonists of the dopamine D4 receptor. They do not showinhibitory effects on the dopamine D2 or D3 receptor.

The unexpected advantage of the compounds of formula I and particularlywith R═H and F in 4-position of the phenyl ring, i.e. is indeed theirlack of any antagonstic effects on dopamine D2 (and D3) receptors. Instrong contrast to the D4 receptor, antagonistic properties at thedopamine D2 receptor and—even if less pronounced D3 receptors—areassociated with the induction of various extrapyramidal motordisturbances which are to be treated with the compounds of formula I.

The principle of the preparation of the aminomethyl chromans of formulaI to be used according to the invention is disclosed in U.S. Pat. No.5,767,132. U.S. Pat. No. 5,767,132 is herein incorporated by reference.

Analoguosly to the method described in U.S. Pat. No. 5,767,132,compounds of formula I according to claim 1 and their optical isomersand/or their pharmaceutical acceptable salts and solvates can beprepared e.g. in that

(a) a compound of formula II

in which G is Cl, Br, I, alkylsulfonyloxy having 1 to 6 C-atoms orarylsulfonyloxy having 6 to 10 C-atoms and R is a hydroxy protectinggroup is reacted with an amine of formula III

and, optionally, cleaving the hydroxy protecting group to obtaincompounds of formula I, in which R═H;or

(b) a compound of formula IV, prepared as described in U.S. Pat. No.5,767,132

in which alkyl is an alkyl group having 1 to 4 C atoms, is dealkylatedwith a dealkylating agent to obtain compounds of formula I, in whichR═H.

Especially preferred is a method (c) to obtain compounds of formula IA

having a defined stereochemistry, wherein a chromaneamine of the formulaV

is reacted with an aldehyde of formula VI

and treated a hydride donor, preferably a complex hydride, such assodium borohydride.

The novel compounds of formula IA are also an object of the presentinvention.

The starting compound of formula V for Method (c) is preferably obtainedby use of a compound of formula VII (obtainable by enantioselectivecatalytic hydrogenation and crystallization according to WO 02/20507)

which is hydrogenated to yield after optional crystallization anenanatiomerically and diastereomerically pure compound of formula VII.

The compound of formula VIII is hydrolysed to the compound of formula Vby standard methods, preferably by treatment with a solution of alkalihydroxide, such as sodium hydroxide.

Surprisingly, in a preferred method for the manufacture of the compoundof formula VIII, the compound of formula VII

is diastereoselectively hydrogenated by a complex hydride, preferablyalkali borohydride such as sodium borohydride in an alcohol, such asmethanol or ethanol, thus leading after optional crystallization anenanatiomerically and diastereomerically pure compound of formula VIII.

This way of hydrogenation of the compound of formula VII has theadvantage of providing the compound VIII with no or only minor amountsof undesired diastereomer VIIIa:

Therefore, the present invention also relates to a process for thepreparation of compounds of formula IA

having a defined stereochemistry, wherein a chromaneamine of the formulaV

is reacted with an aldehyde of formula VI

and treated a hydride donor.

The invention also relates to a process for the preparation of compoundsof formula IB comprising the following steps:

a) hydrogenation of a compound of formula VII

to a compound VIII,

which is and optionally crystallized for purification,

b) hydrolysation of the compound VIII obtained in step a) to a compoundof formula V

c) reaction of a compound of formula V obtained in step b) with acompound of formula VI and treatment with a hydride donor

Preferred is the above method for the preparation of Formula IA, whereinthe hydrogenation of a compound of formula VII to a compound VIII instep a), is performed diastereoselectively by a complex hydride,preferably alkali borohydride such as sodium borohydride in an alcohol,such as methanol or ethanol.

Especially preferred is the above procedure to prepare(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olby using a compound of formula VIA instead of VI

The alkyl group in formula IV is preferably unbranched and has 1, 2, 3,or 4 C atoms, and is preferably methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl or tert-butyl. Particularly preferred is methyl.

In alkylsulfonyloxy having 1 to 6 C-atoms, the alkyl moiety can bemethyl, ethyl, propyl, isopropyl, butyl, pentyl or hexyl. Particularlypreferred for alkylsulfonyloxy is methanesulfonyloxy.

In arylsulfonyloxy having 6 to 10 C-atoms, the aryl moiety can bephenyl, o-, m-, or p- tolyl, o-, m-, or p-ethylphenyl, o-, m-, orp-propylphenyl or naphthyl. Particularly preferred for arylsulfonyloxyis benzenesulfonyloxy, p-toluenesulfonyloxy, naphthalene-1- ornaphthalene-2-sulfonyloxy.

The expression “hydroxyl protective group” is also generally known andrelates to groups which are suitable for protecting a hydroxyl groupagainst chemical reactions, but which are easily removable after thedesired chemical reaction has been carried out at other positions in themolecule.

Typical groups of this type are unsubstituted or substituted aryl,aralkyl, aroyl or acyl groups, furthermore also alkylgroups, alkyl-,aryl- or aralkylsilylgroups or O,O— or O,S-acetals. The nature and sizeof the hydroxyl protective groups is not critical, since they areremoved again after the desired chemical reaction or reaction sequence;groups having 1-20, in particular 1-10 C atoms, are preferred. Examplesof hydroxyl protective groups are, inter alia, benzyl, 4-methoxybenzylor 2,4-dimethoxybenzyl, aroyl groups such as benzoyl or p-nitrobenzoyl,acyl groups such as acetyl or pivaloyl, p-toluolsulfonyl, alkyl groupssuch as methyl or tert-butyl, but also allyl, alkylsilyl groups such astrimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl(TBS) or triethylsilyl, trimethylsilylethyl, aralkylsilyl groups such astert-butydiphenylsilyl (TBDPS), cyclic acetals such as isopropylidene-,cyclopentylidene-, cyclohexylidene-, benzylidene-, p-methoxybenzylidene-or o,p-dimethoxybenzylideneacetal, acyclic acetals such astetrahydropyranyl (Thp), methoxymethyl (MOM), methoxyethoxymethyl (MEM),benzyloxymethyl (BOM) or methylthiomethyl (MTM). Acyl groups having 2 to5 C atoms, such as acetyl, propionyl, butyryl and pivaloyl, areparticularly preferred as hydroxy protecting group in the compounds offormula I according to the invention.

The compounds of formula I can otherwise be prepared by methods knownper se, such as those described in the literature (e.g. in the standardworks such as Houben-Weyl, Methoden der Organisschen Chemie (Methods ofOrganic Chemistry), Georg-Thieme-Verlag, Stuttgart), namely underreaction conditions such as those which are not mentioned in greaterdetail herein.

The compounds of formula II and III are known; the unknown compounds offormula II or III can easily be prepared analogously to the knowncompounds, e.g. those described in the examples of U.S. Pat. No.5,767,132.

The reaction of the compounds of formulae II and III proceeds accordingto methods such as those known from the literature for the alkylation ofamines. The components can be melted together in the absence of asolvent, in a sealed tube or an autoclave if necessary. It is alsopossible, however, to react the compounds in the presence of an inertsolvent. Examples of suitable solvents are hydrocarbons, such asbenzene, toluene or xylene; ketones such as acetone or butanone, etherssuch as tetrahydrofuran or dioxane, amides such as dimethylformamide orn-methylpyrrolidone, or nitrites such as acetonitrile, o else, ifdesired mixtures of these solvents with one another or mixtures withwater. It can be favourable to add an acid-binding agent, for example analkali metal or alkaline earth metal hydroxide, carbonate or bicarbonateor another alkali metal or alkaline earth metal salt of a weak acid,preferably a potassium, sodium or calcium salt, or to add an organicbase such as triethylamine, dimethylaniline, pyridine or quinoline, oran excess of he amine compound. The reaction time is between a fewminutes and 14 days, depending on the conditions used, and the reactiontemperature is between about 0 and 150° C., normally between 20 and 130°C.

Preferred compounds in the context of the invention are those of thegeneral formula I

where

OR is in the 4-, 7-, or 8-position of the chromane system and F is inthe 4-position of the phenyl ring.

Therefore, preferred compounds are2-({([5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-7-ol,2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-8-ol,or their optical isomers or physiologically acceptable salts orsolvates, such as

-   -   a)        (2R/S),4R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,    -   b)        (2S,4R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,    -   c)        (2S,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,    -   d)        (2S,4S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,    -   e)        (2R,4R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,    -   f)        (2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,    -   g)        (2R,4S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,    -   h)        (2R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-7-ol,    -   i)        (2R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-7-ol,    -   j)        (2S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-7-ol,    -   k)        (2R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-8-ol,    -   l)        (2R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-8-ol,    -   m)        (2S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-8-ol,    -   or a physiologically acceptable salt or solvate thereof.

Particularly preferred compounds of formula I are the compounds selectedfrom the group consisting of

-   -   a)        (2R/S),4R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,    -   b)        (2S,4R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,    -   c)        (2S,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,    -   d)        (2S,4S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,    -   e)        (2R,4R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,    -   f)        (2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,    -   g)        (2R,4S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,    -   or a physiologically acceptable salt or solvate thereof.

The most particularly preferred compound of formula I is(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt or solvate thereof.

In the context of the present invention, the aminomethyl chromancompounds of formula I can be present in various stereoisomeric forms,i.e. in the form of their (+) or (−) enantiomers or as a mixture ofthese enantiomers (racemate). For the separation of the racemates intothe enantiomeric forms, reference is made to the relevant, knownspecialist literature.

In the context of the present invention, the physiologically acceptablesalts can also be employed. Physiologically acceptable salts of thesubstituted 2-aminomethyl chromans of formula I can be salts of thecompounds according to the invention with suitable organic or inorganicacids, in particular mineral acids, carboxylic acids or sulphonic acids.Particularly preferred salts are, for example, those with hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid,benzenesulphonic acid, naphthalene-disulphonic acid, acetic acid,propionic acid, lactic acid, tartaric acid, citric aid, fumaric acid,maleic acid or benzoic acid.

A preferred salt of2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor its optical isomers is the monohydrochloride or the monohydrochloridehemihydrate.

A preferred salt of2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-7-olor its optical isomers is the hydrobromide or the maleate.

A preferred salt of2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-8-olor its optical isomers is the hydrobromide or the maleate.

The invention had the object of providing novel uses for substitutedaminomethyl chromans of formula I, their optical isomers and/or theirphysiologically acceptable salts and solvates.

It has been found that substituted aminomethyl chromans of formula I

in which

R represents hydrogen or a hydroxyl protecting group, and their opticalisomers and pharmaceutically acceptable salts or solvates, in particular2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-7-ol,2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-8-ol,or an optical isomer or a physiologically acceptable salt or solvatethereof, have therapeutic activity against extrapyramidal movementdisorders such as idiopathic Parkinsons's disease, Parkinson syndromes,dyskinetic, choreatic, or dystonic syndromes, tremor, Gilles de laTorette syndrome, ballism, myoclonus, restless legs syndrome orWilsons's disease, as well as extrapyramidal motoric disturbances[synonymous extrapyramidal symptoms (EPS)] induced by neuroleptics.

Additionally it has been found that substituted aminomethyl chromanes offormula I

in which

R represents hydrogen or a hydroxyl protecting group, and their opticalisomers and pharmaceutically acceptable salts or solvates, in particular2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-7-ol,2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-8-ol,or an optical isomer or a physiologically acceptable salt or solvatethereof, have therapeutic activity against adverse effects ofanti-Parkinsonian drugs in extrapyramidal movement disorders, inparticular against dopaminomimetic adverse effects of anti-Parkinsoniandrugs in idiopathic Parkinson's disease or Parkinson syndromes.

It has been found that substituted aminomethyl chromans of formula I

in which

R represents hydrogen or a hydroxyl protecting group, and their opticalisomers and pharmaceutically acceptable salts, in particular2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor an optical isomer or a physiologically acceptable salt or solvatethereof, excert an extraordinary potency in reversing catalepsy.Extrapyramidal motor side effects in e.g. rodents are measured by theability of a drug to induce catalepsy. Catalepsy is defined as a statewhere an animal continues to remain in an unnormal (nonphysiological‘uncomfortable’) posture for a long time (e.g.: M. E. Stanley and S. D.Glick, Neuropharmacology, 1996; 15: 393-394; C. J. E. Niemegeers and P.Janssen, Life Sci., 1979, 201-2216). For example, if a hindpaw of a ratis placed on an elevated level, e.g. a platform elevated 3 cm aboveground level, a normal rat immediately withdraws the hindpaw from theplatform to the ground level. A cataleptic rat remains in this unnaturalposture even for minutes.

Beneficial effects on the extrapyramidal motoric system have previouslybeen described for other drugs with 5-HT_(1A) agonistic action.Buspirone for example, which is an anxiolytic drug by nature, exhibitsmoderate anti-dyskinetic properties in advanced Parkinson patients (B.Kleedorfer et al., J Neurol Neurosurg Psychiatry, 1991, 54: 376-377; V.Bonifati et al., Clin Neuropharmacol, 1994, 17: 73-82). The mainmechanism of action is obviously via stimulation of 5-HT_(1A) receptorsof the raphe nigral and raphe striatal pathways.

Likewise, the antipsychotic drug clozapine, which has very high affinityfor the dopamine D4 but also for a variety of other receptors, hasdemonstrated beneficial antidyskinetic effects in Parkinson patients(e.g. Durif F et al., Neurology 1997; 48: 658-662). More recently, theexperimental compound8-methyl-6-(4-methyl-1-piperazineyl)-11H-pyrido[2,3-b][1,4,]benzodiazepine,a structural analog of clozapine with much increased selectivity for thedopamine D4 receptor compared to clozapine itself (Liegeois J F et al.,Eur. J. Pharmacol. 1995; 273: R1-R3), has been demonstrated to havebeneficial effects in parkinsonian monkeys (Tahar A H et al., Eur. J.Pharmacol. 2000; 399: 183-186).

In rats, the subcutaneous ED₅₀ value (i.e. the calculated dose toreverse catalepsy by 50%) for(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olis about 2 mg/kg which is comparable or even more potent compared toother 5-HT_(1A) agonists such as ipsapirone (ED₅₀ 10 mg/kg) or buspirone(ED₅₀ 6 mg/kg) and the D4 antagonist8-methyl-6-(4-methyl-1-piperazineyl)-11H-pyrido[2,3-b][1,4,]benzodiazepine (ED₅₀ 3 mg/kg).

Therefore, the present invention relates to the use of substitutedaminomethyl chromans of formula I and their optical isomers andpharmaceutically acceptable salts or solvates for the manufacture of amedicament for the treatment of extrapyramidal movement disorders.

Therefore, the invention especially relates to the use of(2R,4R)-2-({[5-(4-flurophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmacologically acceptable salt or solvate for the manufacture ofa medicament for the treatment of extrapyramidal movement disorders.

A preferred salt of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olis(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Therefore, the invention especially relates to the use for themanufacture of a medicament for the treatment of extrapyramidal movementdisorders in which the pharmacologically acceptable salt is(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Additionally, the invention relates to the use of a pharmaceuticalcomposition containing at least(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its biocompatible salts or solvates for the treatment ofextrapyramidal movement disorders.

A compound of formula I according to claim 1 or a physiologicallyacceptable salt or solvate thereof, useful for the treatment ofextrapyramidal movement disorders, in particular for the treatment ofidiopathic Parkinson's disease, Parkinson syndromes, dyskinetic,choreatic or dystonic syndromes, extrapyramidal motoric adverse effectsof neuroleptics, tremor, Gilles de la Tourette syndrome, ballism,myoclonus, restless legs syndrome or Wilson's disease and/or useful forthe treatment of adverse effects in idiopathic Parkinson's disease orParkinson syndromes including medicinal compositions as defined below,is preferably administered in doses from 0.1 to 100 mg, preferentiallybetween approximately 1 and 20 mg. The composition may be administeredonce or more times a day, e.g. 2, 3, or 4 times daily. The specific dosefor each patient depends on all sorts of factors, e.g. on the activityof the specific compound employed, on the age, body weight, generalstate of health, on sex, diet, time and route of administration, on theexcretion rate, pharmaceutical substance combination and on the severityof the particular disorder to which the therapy relates. Oraladministration is preferred, but also parenteral routes ofadministration (e.g. intravenous or transdermal) can be utilized.

Anti-Parkinsonian drugs are conventional drugs such as l-dopa (levodopa)and l-dopa combined with a decarboxylase inhibitor such as benserazideor carbidopa, dopamine agonists such as bromocriptine, apomorphine,cabergoline, pramipexol, ropinirol, pergolide, dihydro-α-ergocriptine orlisuride plus all drugs acting via stimulation of dopamine receptors,inhibitors of catechol-O-methyl transferase (COMT) such as entacapone ortolcapone, inhibitors of monoamine oxidase (MAO) such as selegiline andantagonists of N-methyl-D-aspartate (NMDA) receptors such as amantadineor budipine.

Adverse effects of said anti-Parkinsonian drugs are all types ofdyskinesias, such as choreic, dystonic, ballistic and myoclonicdyskinesia, as well as motor (response) fluctuations or psychoticstates, such as optical or acoustical hallucinations.

Therefore, the present invention relates to the use of substitutedaminomethyl chromans of formula I and their optical isomers andpharmaceutically acceptable salts or solvates for the manufacture of amedicament for the treatment of adverse effects of anti-Parkinsoniandrugs in idiopathic Parkinson's disease.

Therefore, the invention especially relates to the use of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmacologically acceptable salt or solvate for the manufacture ofa medicament for the treatment of adverse effects of anti-Parkinsoniandrugs in idiopathic Parkinson's disease.

Treatment of adverse effects of conventional anti-Parkinsonian drugs asdefined above are determined in a modification of the animal model ofthe Parkinsonian cynomolgus monkey according to P. J. Blanchet et al.,Exp. Neurology 1998; 153: 214-222. Monkeys render parkinsonian byrepeated injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP). The Parkinsonian monkeys are chronically treated with thestandard 1-dopa therapy according to P. J. Blanchet et al., Mov.Disord., 1998; 13: 798-802. Longterm treatment with l-dopa inducesextrapyramidal motor side effects and psychotic states which are bothqualitatively and quantitatively, assessed by the Abnormal InvoluntaryMovement Scale (P. J. Blanchet et al., Mov. Disord. 1998; 13: 798-802)for different body parts (face, neck, trunk, each limb) and by ratingfor psychotic states by observing the monkey's attention, reactivity andmobility.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olreduce overall choreiform dyskinesias and dystonic dyskinesias as wellas psychotic states.

A typical study to investigate the efficacy of the compounds accordingto the invention for adverse effects in Parkinson's disease is describedin the following. 40 patients of either sex with advanced idiopathicParkinson's disease complicated by “peak-dose” dyskinesia participate ina double-blind study. The main inclusion criteria are Hoehn & Yahr stage≧2.5 (lit.: Hoehn H. M. et al, Neurology 1967; 17: 427-442), aged 40-75years, symptom duration of at least 5 years, and a l-dopa treatmentduration of at least 3 years.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate or placebo is administered as “add on” tothe conventional Parkinson treatment, which is maintained unchangedduring the whole study. The dose of blinded medication is titrated overa period of 3 weeks in a range from 2.5 to 10 mg b.i.d. Then themedication is kept constant for 3 weeks. Before the start of titrationand at the end of the treatment period the patients fill a diary card in30 min. inervals for 48 hours. The diary card differentiates 5 differentstates: (1) “on” without dyskinesia, (2) “on” with troublesomedyskinesia, (3) “on” with non-troublesome dyskinesia, (4) “off” time,and (5) time asleep (Hauser R A et al., Clin. Neuropharmacol., 2000, 23,75-81). The primary outcome variable of the protocol is the change in“on” time with troublesome dyskinesia. The statistical analysis of thediary data demonstrates a significant reduction in “on” time withtroublesome dyskinesia under treatment with(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate while the “on” time without dyskinesiasignificantly increase. The other parameters are not changed.

A preferred salt of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olis(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Therefore, the invention especially relates to the use for themanufacture of a medicament for the treatment of adverse effects ofanti-Parkinsonian drugs in idiopathic Parkinson's disease in which thepharmacologically acceptable salt is(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Additionally, the invention relates to the use of a pharmaceuticalcomposition containing at least one compound of(2R,4R)-2-({[5-(4-fluorophenylpyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its biocompatible salts or solvates for the treatment ofadverse effects of anti-Parkinsonian drugs in idiopathic Parkinson'sdisease.

Furthermore, the present invention relates to the use of substitutedaminomethyl chromans of formula I and their optical isomers andpharmaceutically acceptable salts or solvates for the manufacture of amedicament for the treatment of idiopathic Parkinson's disease.

Therefore, the invention especially relates to the use of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmacologically acceptable salt or solvate for the manufacture ofa medicament for the treatment of idiopathic Parkinson's disease.

A typical animal model for idiopathic Parkinson's disease is theParkinsonian cynomolgus monkey according to P. J. Blanchet et al., Exp.Neurology 1998; 153: 214-222. Monkeys render parkinsonian by repeatedinjections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).Parkinsonian symptoms are qualitatively assessed by the use of the LavalUniversity Disability Scale (B. Gomez-Mancilla et al., 1993; Mov.Disord. 8: 144-150) measuring the following symptoms: posture, mobility,climbing, gait, holding food, vocalizing, grooming, social interaction.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olreduce all the parkinsonian symptoms and increased total activity.

A typical study to investigate the efficacy of the compounds accordingto the invention in the treatment of idiopathic Parkinson's disease isdescribed in the following. 180 patients of either sex with idiopathicParkinson's disease participate in a double-blind study. The maininclusion criteria are Hoehn & Yahr stage ≧2.0 (Hoehn H. M. et al,Neurology 1967; 17: 427442), aged 50-80 years, symptom duration of atleast 5 years.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate or placebo is administered as “add on” tothe conventional Parkinson treatment, which is maintained unchangedduring the whole study. The dose of blinded medication is titrated overa period of 4 weeks in a range from 2.5 to 10 mg b.i.d. Then themedication is kept constant for 1 week. Before the start of titrationand at the end of the treatment period the patients fill a diary card in30 min. intervals for 48 hours. The diary card differentiates 5different states: (1) “on” without dyskinesia, (2) “on” with troublesomedyskinesia, (3) “on” with non-troublesome dyskinesia, (4) “off” time,and (5) time asleep (Hauser R A et al., Clin. Neuropharmacol., 2000, 23,75-81). This allows to detect simultaneously a beneficial effect of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt or solvate thereof, in particularof(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate, on the global motoric function, ondystonia, motor fluctuations, and on psychosis. Furthermore, theefficacy to treat tremor is shown. The analysis demonstrates asignificant clinical improvement under treatment with(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

A preferred salt of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olis(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Therefore, the invention especially relates to the use for themanufacture of a medicament for the treatment of idiopathic Parkinson'sdisease in which the physiologically acceptable salt is(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Additionally, the invention relates to the use of a pharmaceuticalcomposition containing at least one compound of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its biocompatible salts or solvates together with at least onesolid, liquid or semiliquid excipient or adjunct for the treatment ofidiopathic Parkinson's disease.

The limiting factor of Parkinson treatment with l-dopa and/or dopamineagonists is often the occurence of psychosis or dyskinesia and othermotor fluctuations.

It has been found that compounds of formula I according to claim 1 orphysiologically acceptable salts or solvates thereof enhance theanti-Parkinsonian effect of anti-Parkinsonian drugs as defined abovewithout inducing extrapyramidal side effects.

Therefore, the add-on therapy with in particular(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmaceutically acceptable salt or solvate thereof, in particularof(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate, now opens the possibility to increase thedoses of l-dopa and/or dopamine agonists and/or all otheranti-Parkinsonian drugs as defined above in order to counteract periodsof insufficient motility (“off” phases) without provoking the abovementioned side effects. That represents an entirely novel approach inthe treatment of Parkinson's disease leading to a significant benefitfor the patients.

Thus, the invention relates to a pharmaceutical composition comprising,as active principles, (i) a compound according to claim 11 or 12, and(ii) at least one anti-Parkinsonian drug, in combination with one ormore pharmaceutically acceptable excipients.

Particularly, the invention relates to a pharmaceutical compositioncomprising, as active principles, (i)(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmaceutically acceptable salt or solvate, and (ii) l-dopa.

Thus, the invention relates to a pharmaceutical composition comprising,as active principles, (i) a compound according to claim 11 or 12, (ii)at least one anti-Parkinsonian drug, and at least (iii) onedecarboxylase inhibitor, in combination with one or morepharmaceutically acceptable excipients.

Particularly, the invention relates to a pharmaceutical compositioncomprising, as active principles, (i)(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmaceutically acceptable salt or solvate, (ii) l-dopa and (iii)benserazide or carbidopa, in combination with one or morepharmaceutically acceptable excipients.

The ratios of the respective amounts of a compound according to claim 11or 12 and of the conventional anti-Parkinsonian drug, optionallytogether with an decarboxylase inhibitor thus vary in consequences.Preferably, the weight ratio of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its physiologically acceptable salts or solvates to theconventional anti-Parkinsonian drug ranges from 1:1 to 1:100, preferablyfrom 1:10 to 1:90 and better still from 1:40 to 1:60.

Another subject of the present invention is additionally the use of acompound of formula I according to claim 1, in particular of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its physiologically acceptable salts or solvates, incombination with at least one anti-Parkinsonian drug, for thepreparation of a medicinal combination intended to enhance theanti-Parkinsonian effect of said anti-Parkinsonian drugs.

According to the invention, the term “medicinal combination” is intendedto refer either to a pharmaceutical composition as defined above, inwhich the two active principles or compounds are the essentialconstituents of the same composition, or to a kit comprising twoseparate compositions, the first comprising for example(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its physiologically acceptable salts or solvates as soleactive principle, and the second comprising at least oneanti-Parkinsonian drug as active compound.

When the medicinal combination is in the form of a kit, theadministration of the two compositions constituting this kit, althoughcarried out separately, is simultaneous for a combined therapy. It ispreferred to use(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olin the form of the monohydrochloride hemihydrate.

Adverse effects of anti-Parkinsonian drugs as defined above areadditionally known in particular in Parkinson syndromes.

Parkinson syndromes are e.g. multiple system atrophies (MSA),Steele-Richardson-Olszewski syndrome (=progressive supranuclear palsy),cortico-basal degeneration, olivo-ponto cerebellar atrophy or Shy Dragersyndrome.

Therefore, the invention relates to the use of substituted aminomethylchromans of formula I and their optical isomers and pharmaceuticallyacceptable salts or solvates for the manufacture of a medicament for thetreatment Parkinson syndromes and/or for the treatment of adverseeffects of anti-Parkinsonian drugs in Parkinson syndromes.

Therefore, the invention especially relates to the use of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmacologically acceptable salt or solvate for the manufacture ofa medicament for the treatment of Parkinson syndromes and/or for thetreatment of adverse effects of anti-Parkinsonian drugs in Parkinsonsyndromes.

A typical animal model is the reserpinized rat or mouse (e.g. M. S.Starr and B. S. Starr, J. Neural Transm.—Park. Dis. Dement. Sect., 1994;7: 133-142; M. Gossel et al., J. Neural Transm.—Park. Dis. Dement.Sect., 1995; 10: 27-39; N. R. Hughes et al., Mov. Disord., 1998; 13:228-233). Reserpine is a potent depleter of monoamines and producesnearly complete akinesia in both species. Prominent 24 h afterapplication, the distance travelled and the time active is nearly zeroas measured in conventional activity meters.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmaceutically acceptable salt or solvate thereofdose-dependently reduce akinesia, i.e. restored distance travelled andtime active to about the level of normal animals.

Another more recent animal model is the striatonigral degenerationapproach in the rat according to G. K. Wenning et al., J. Neural Transm.Suppl., 1999; 55: 103-113. Rats receive an unilateral injection of6-hydroxydopamine into the left medial forebrain bundle followed by aninjection of quinolinic acid into the ipsilateral striatum inducingnigrostriatal degeneration. The degeneration results in turning behaviorto a challenge with dopaminomimetics such as apomorphine or amphetamine.Turning behavior is measured by an automated recorder. Turning behaviorinduced by apomorphine or amphetamine is dose-dependently antagonized by(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmaceutically acceptable salt or solvate thereof.

Multiple system atrophy (MSA) is due to an expansive neurodegenerationin the extrapyramidal and autonomic nervous system which leads to anakinetic Parkinsonian syndrome with vegetative disturbances. In contrastto idiopathic Parkinson's disease the density of central dopaminereceptors is markedly decreased and therefore, MSA patients poorlyrespond to dopaminergic drugs. Since(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmaceutically acceptable salt or solvate thereof actpredominantly via serotonin receptors on the extrapyramidal system, theyare able to improve the motor performance in these otherwise mostlyuntreatable patients.

A typical study to investigate the efficacy of the compounds accordingto the invention in MSA patients encompasses 30 patients of either sexwith a symptom duration of at least 5 years and a significant reductionof central dopamine receptors in positron emission tomography (PET)scan. The study design is similar to that described above forParkinson's disease.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate or placebo is titrated as “add on” to theconventional treatment (dose range 2,5 to 20 mg b.i.d.). After adouble-blind dose-finding phase of 3 weeks during which the individualdose is identified for each patient on the basis of tolerability andefficacy, the dose is maintained unchanged for 3 additional weeks.Before the start of titration and at the end of the treatment period acomplete UPDRS assessment is performed in each patient (primary outcomemeasure). Statistical analysis of UPDRS demonstrates a significantclinical improvement of Parkinson symptoms under treatment with(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

A preferred salt of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olis(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Therefore, the invention especially relates to the use for themanufacture of a medicament for the treatment of Parkinson syndromesand/or for the treatment of adverse effects of anti-Parkinsonian drugsin Parkinson syndromes in which the pharmacologically acceptable salt is(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Additionally, the invention relates to the use of a pharmaceuticalcomposition containing at least one compound of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its biocompatible salts or solvates for the treatment ofParkinson syndromes and/or for the treatment of adverse effects ofanti-Parkinsonian drugs in Parkinson syndromes.

The present invention relates furthermore to the use of substitutedaminomethyl chromans of formula I and their optical isomers andpharmaceutically acceptable salts or solvates for the manufacture of amedicament for the treatment of dyskinetic and/or choreatic syndromes.

Therefore, the invention especially relates to the use of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmacologically acceptable salt or solvate for the manufacture ofa medicament for the treatment of dyskinetic and/or choreatic syndromes.

Dyskinetic and/or choreatic syndromes are e.g. Huntington's disease,minor chorea or chorea of pregnancy.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt or solvate thereof are inparticular useful for the treatment of Huntington's disease.

A typical animal model is the systemic 3-nitropropionic acid (3-NP)model in rats according to C. V. Borlongan et al., Brain Res., 1995;697: 254-257. Rats are treated with injections of the selective striatalneurotoxin 3-NP i.p. every fourth day (C. V. Borlongan et al., BrainRes. Protocols, 1997; 1: 253-257). After two injections of 3-NP, ratsdisplay nocturnal hyperactivity reflecting symptoms of earlyHuntington's disease, whereas rats treated with four injections of 3-NPdisplay nocturnal akinesia (hypoactivity) reflecting symptoms of lateHuntington's disease. Nocturnal activity is automatically measured inconventional acitivity cages by infrared beams.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmaceutical acceptable salt or solvate thereof reduce both thenocturnal hyperactivity and akinesia.

A typical trial to establish the effect of the compounds according tothe invention on chorea, voluntary motor performance, and functionaldisability in patients with Huntington's disease encompasses 32genetically diagnosed patients.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate or placebo is administered as “add on” tothe conventional treatment, which is maintained unchanged during thewhole study. The dose of blinded medication is titrated over a period of3 weeks in a range from 2.5 to 20 mg b.i.d. Then the medication is heldconstant for 1 week. Assessments are performed in the week before and atthe last day of the trial. Chorea is scored using the abnormalinvoluntary movement scale (AIMS, W. Guy, in: ECDEU assessment manual.Rockville Md.: US dept. of health, education and welfare, 1976:534-537), the unified Huntington's disease rating scale (UHDRS,Huntington study group, 1996, Movement Disord, 11: 13642), and judgementof video recordings. Voluntary motor performance is assessed using theUHDRS motor scale. Patients and their partners complete a questionnaireregarding functional disability. Statistical analysis demonstratessignificant improvement of voluntary and involuntary motor performancein Huntington patients under treatment with(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt thereof.

A preferred salt of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olis(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Therefore, the invention especially relates to the use for themanufacture of a medicament for the treatment of dyskinetic and/orchoreatic syndromes, in particular for the treatment of Huntington'sdisease, in which the pharmacologically acceptable salt is(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Additionally, the invention relates to the use of a pharmaceuticalcomposition containing at least one compound of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its biocompatible salts or solvates for the treatment ofdyskinetic and/or choreatic syndromes.

The present invention relates to the use of substituted aminomethylchromans of formula I and their optical isomers and pharmaceuticallyacceptable salts or solvates for the manufacture of a medicament for thetreatment of dystonic syndromes.

Therefore, the invention especially relates to the use of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmacologically acceptable salt or solvate for the manufacture ofa medicament for the treatment of dystonic syndromes.

Dystonic syndromes are e.g. spasmalic torticollis, writer's cramp,blepharospasm, Meige syndrome or dopasensitive dystonia.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt or solvate thereof is in particularuseful for the treatment of spasmalic torticollis and/or blepharospasm.

A typical animal model is the mutant dystonic hamster according to A.Richter and W. Löscher, Prog. Neurobiol. 1998; 54: 633-677. In thisgenetically dystonic hamsters, dystonic attacks are provoked by takingthe animal from the home cage and placing it on a balance. The dystonicsyndrome consists of a sequence of abnormal movements, and the severityof the single symptoms is rated by a scoring system.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmaceutically acceptable salt or solvate thereofdose-dependently reduce the severity of dystonic symptoms.

To demonstrate the efficacy of the compounds according to the inventionin dystonic syndromes, a double-blind, placebo-controlled study isperformed in patients with cervical dystonia (spasmodic torticollis) whodo not tolerate injection of botulinum toxin.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate is titrated as described above in therange from 2.5 mg to 20 mg b.i.d. The Toronto western spasmodictorticollis rating scale (TWSTRS, C. L. Comella et al., 1997, MovementDisord, 12: 570-575) is used as primary outcome measure. A significantimprovement in the TWSTRS scores is noted for the patients treated with(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its pharmaceutically acceptable salts or solvates.

A preferred salt of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olis(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Therefore the invention especially relates to the use for themanufacture of a medicament for the treatment of dystonic syndromes, inparticular of spasmalic torticollis and/or blepharospasm, in which thepharmacologically acceptable salt is(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Additionally, the invention relates to the use of a pharmaceuticalcomposition containing at least one compound of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its biocompatible salts or solvates for the treatment ofdystonic syndromes.

The present invention relates to the use of substituted aminomethylchromans of formula I and their optical isomers and pharmaceuticallyacceptable salts or solvates for the manufacture of a medicament for thetreatment of extrapyramidal symptoms induced by neuroleptics.

Therefore, the invention especially relates to the use of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmacologically acceptable salt or solvate for the manufacture ofa medicament for the treatment of extrapyramidal symptoms induced byneuroleptics.

Extrapyramidal motoric disturbances induced by neuroleptics are e.g.early dyskinesia, dystonia, akathisia, parkinsonoid, in particularbradykinesia, or tardive dyskinesia.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt or solvate thereof are usefulparticularly for the treatment of akathisia and/or tardive dyskinesiaand/or parkinsonoid.

A typical animal model is neuroleptics-induced muscle rigidity in ratsaccording to S. Wolfarth et al., Arch. Pharmacol. 1992; 345: 209-212.Rats are challenged with the conventional neuroleptic drug haloperidolwhich enhances muscle tone. Muscle tone is electromechanically measuredas the resistence to passive flexion and extension of the hind limb.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmaceutically acceptable salt or solvate thereof decrease themuscle tone enhanced by haloperidol.

Another typical animal model is the neuroleptics sensitized monkeyaccording to D. E. Casey, Psychopharmacology, 1996; 124: 134-140.Monkeys treated repeatedly with conventional neuroleptics are highlysensitive to a subsequent challenge dose of neuroleptic drugs. Whenchallenged, the monkeys immediately show extrapyramidal motor sideeffects such as dystonia, dyskinesias, akathisia, and bradykinesia whichare rated by a scoring system. The conventional neuroleptic drughaloperidol is given as a challenge. When the before-mentionedextrapyramidal motor side effects occur,(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmaceutically acceptable salt or solvate thereof isadministered;(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-oldose-dependently reduce the extrapyramidal motor side effects.

Tardive dyskinesia is a common adverse effect of long-term treatmentwith neuroleptics. A typical study to investigate the efficacy of thecompounds according to the invention in tardive dyskinesia is describedin the following. 32 schizophrenic (DSM-III-R) inpatients aged 25-60years on long-term stable antipsychotic treatment (duration of at least5 years) entered the study.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate or placebo is administered as “add on” tothe antipsychotic treatment, which is kept constant during the wholestudy. The dose of blinded medication is titrated over a period of 3weeks in a range from 2,5 to 20 mg b.i.d. Then the medication ismaintained under double-blind conditions for 2 weeks. After a 2-weekwash-out period, the test drugs are crossed over. Assessments of tardivedyskinesia by means of the Abnormal Involuntary Movement Scale (AIMS,see above) and of Parkinsonian extrapyramidal side effects (UPDRS, seeabove) are made pretreatment and posttreatment. AIMS scores duringtreatment with(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate are significantly lower than duringplacebo period.

A preferred salt of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olis(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Therefore, the invention especially relates to the use for themanufacture of a medicament for the treatment of extrapyramidal symptomsinduced by neuroleptics, in particular of akathisia and/or tardivedyskinesia, in which the pharmacologically acceptable salt is(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Additionally, the invention relates to the use of a pharmaceuticalcomposition containing at least one compound of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its biocompatible salts or solvates for the treatment ofextrapyramidal symptoms induced by neuroleptics.

The present invention relates to the use of substituted aminomethylchromans of formula I and their optical isomers and pharmaceuticallyacceptable salts or solvates for the manufacture of a medicament for thetreatment of tremor.

Therefore, the invention especially relates to the use of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmacologically acceptable salt or solvate for the manufacture ofa medicament for the treatment of tremor.

Tremor includes all types of tremors such as essential tremor, activatedphysiological tremor, cerebellar tremor, orthostatic tremor ordrug-induced tremor.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt or solvate thereof are particularlyuseful for the treatment of essential tremor and/or drug-induced tremor.

Typical animal models utilize either genetic mutant animals or aremodels where tremor is induced by a pharmacological agent (for review:H. Wilms et al., Mov. Disord., 1999; 14: 557-571).

Typical genetic models in mutant animals are the Campus Syndrome in thePietrain pig according to A. Richter et al. (Exp. Neurology, 1995; 134:205-213) or the Weaver mutant mouse according to J. R. Simon and B.Ghetti (Mol. Neurobiol., 1994; 9: 183-189). In the Campus Syndromemodel, these mutant pigs show a high-frequency tremor when standing andduring locomotion, but not while lying at rest. Assessment of tremor ismade by accelerometric recording. In the Weaver mutant mouse,degenerative cerebellar atrophy is could in association with tremor,gait instability, and toppling over the sides after a few steps. Gaitdisability and toppling result in dramatically reduced locomotoractivity measured by the distance travelled and the time spent withambulation in conventional activity cages.

(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its pharmaceutically acceptable salts or solvates improve theCampus Syndrome in the Pietrain pig, i.e. reduce disabling tremor whenstanding and during locomotion, and enhance locomotor activity in theWeaver mutant mouse.

A typical animal model for drug-induced tremors is theoxotremorine-induced tremor (e.g. H. Hallberg and O. Almgren, ActaPhysiol. Scand., 1987; 129: 407-13; J. G. Clement and W. R. Dyck, J.Pharmacol. Meth., 1989; 22: 25-36). Oxotremorine induces tremor which ismeasured by a rating scale.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its pharmaceutically acceptable salts or solvates inhibitoxotremorine-induced tremors.

A preferred salt of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olis(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Therefore, the invention especially relates to the use for themanufacture of a medicament for the treatment of tremors, in particularof essential tremors and/or drug-induced tremors, in which thepharmacologically acceptable salt is(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Additionally, the invention relates to the use of a pharmaceuticalcomposition containing at least one compound of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its biocompatible salts or solvates for the treatment oftremor.

The present invention relates to the use of substituted aminomethylchromans of formula I and their optical isomers and pharmaceuticallyacceptable salts or solvates for the manufacture of a medicament for thetreatment of extrapyramidal movement disorders chosen from the groupconsisting of Gilles de la Tourette syndrome, ballism, myoclonus,restless legs syndrome and Wilson's disease.

Therefore, the invention especially relates to the use of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a pharmacologically acceptable salt or solvate for the manufacture ofa medicament for the treatment of extrapyramidal movement disorderschosen from the group consisting of Gilles de la Tourette syndrome,ballism, myoclonus, restless legs syndrome and Wilson's disease.

A typical animal model for myoclonus is myoclonus induced by an acutehypoxic episode according to D. D. Truong et al., Mov. Dsiord., 1994; 9:201-206). In this model of posthypoxic myoclonus, rats undergo a cardiacarrest for 8 minutes and are resuscitated thereafter. Myoclonic jerksoccur spontaneously but can be provoked by auditory stimulation, too,worsening over the days following cardiac arrest.(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its pharmacologically acceptable salts or solvatesdose-dependently reduce the number of spontaneous and autitory-evokedmyoclonic jerks.

A preferred salt of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olis(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Therefore, the invention especially relates to the use for themanufacture of a medicament for the treatment of extrapyramidal movementdisorders chosen from the group consisting of Gilles de la Tourettesyndrome, ballism, myoclonus, restless legs syndrome and Wilson'sdisease in which the pharmacologically acceptable salt is(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate.

Additionally, the invention relates to the use of a pharmaceuticalcomposition containing at least one compound of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor one of its biocompatible salts or solvates for the treatment ofextrapyramidal movement disorders chosen from the group consisting ofGilles de la Tourette syndrome, ballism, myoclonus, restless legssyndrome and Wilson's disease.

The extrapyramidal movement disorders such asSteele-Richardson-Olszewski syndrome (=progressive supranuclear palsy),cortico-basal degeneration, olivo-ponto cerebellar atrophy, Shy Dragersyndrome, minor chorea, chorea of pregnancy, writer's cramp,blepharospasm, Meige syndrome, dopa-sensitive dystonia, Gilles de laTourette syndrome, ballism, myoclonus, restless legs syndrome, andWilson's disease are not frequent enough to perform regular double-blindtrials. However, the medical need in this field is pressing since nosufficient therapies are available so far.

Therefore, open-label observations in few selected patients are anadequate method to demonstrate the efficacy of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt or solvate thereof.

All the pharmaceutical preparations used for the treatment ofextrapyramidal movement disorders and/or for the treatment of adverseeffects of anti-Parkinsonian drugs in extrapyramidal movement disordersincluding the medicinal combination can be used as pharmaceuticals inhuman or veterinary medicine.

The compositions of the invention are preferably administeredparenterally, or better still orally, although the other routes ofadministration, for instance such as rectal administration, are notexcluded.

Suitable excipients are organic or inorganic substances which aresuitable for enteral (e.g. oral), parenteral or topical administrationand which do not react with a compound of formula I according to claim 1such as(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-oland/or one of its biocompatible salts or solvates, for example water,vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols,glycerol triacetate, gelatine, carbohydrates such as lactose or starch,magnesium stearate, talc, petroleum jelly. Forms which are used for oraladministration are, in particular, tablets, pills, sugar-coated tablets,capsules, powders, granules, syrups, liquids or drops, forms for rectaladministration are, in particular suppositories, forms for parenteraladministration are, in particular, solvents, preferably oily or aqueoussolutions, furthermore suspensions, emulsions or implants, and forms fortopical administration are transdermal plasters, ointments, creams orpowders. The compounds of formula I according to claim 1 and/or theirpharmaceutically acceptable salts and solvates may also be lyophilizedand the resulting lyophilisates used for example for the preparation ofinjectable products. The abovementioned preparations can be insterilized form and/or comprise auxiliaries such as glidants,preservatives, stabilizers and/or wetting agents, emulsifiers, salts formodifying the osmotic pressure, buffer substances, colourings,flavourings and/or other active ingredients, e.g. one or more vitamins.

Preparations may, if desired, be designed to give slow release of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a biocompatible salt or solvate thereof.

EXAMPLES Example 1(2R,4R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol

A stirred suspension of 3,5 g(2R,4R/S)-2-chloromethyl-4-hydroxy-chromane in 200 ml acetonitrile istreated with 4.5 g triethylamine to yield a yellow solution. To thissolution 4 g sodium bicarbonate and 4 g3-(4-fluorophenyl)-pyridyl-5-methylammonium hydrochloride in 100 mlacetonitrile is added. The reaction mixture is refluxed over night toyield a red solution. The mixture was evaporated, the resulting residueis taken up with ethyl acetate and washed with water and dried withsodium sulfate. The organic solution is evaporated to dryness. Theresulting residue is purified by chromatography. The pure compound isconverted to(2R,4R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olhydrochloride in ethanol. Fp. 165 degrees C. The yield was 800 mg.Besides the N-monoalkylated compound, N-dialkylated and startingmaterial is obtained.

Example 2(2R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-7-ol

1. 300 mg of(2R/S)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-7-methoxychromanis treated with 25 ml hydrobromic acid (48% in water) at 130 degrees C.The obtained red solution is neutralized and worked up as described inexample 1. 130 mg of(2R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-7-olhydrobromide is obtained;

RF=0.27 in ethyl acetate/methanol 8/2.

Similarly,2-({[5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-amino}-methyl)-chroman-7-olas maleate is obtained.

2. Analoguosly to example 2.1,(2R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-8-methoxychromanis treated with hydrobromic acid to obtain(2R/S)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-8-olhydrobromide.

Example 3

During 2 hours, a total of 26.0 g sodium borohydride was added in smallportions to the stirred mixture of 20.0 g of a compound of formula VIIin 250 ml of methanol. After stirring the mixture for one hour at roomtemperature, 500 ml of water and 800 ml of ethylacetate was added. Theorganic layer was separated, the solvent removed and the residuesubjected to conventional work-up. After crystallization from toluene,the enatiomerically and diastereomerically pure compound of formula VIIIwas obtained.

Example 4

A solution of 3.7 g aldehyde VIA and 3.3 g amine V (obtainable accordingto WO 02/20507, Example 3 (2), from a compound of formula VIII) and acatalytic amount of p-toluenesulfonic acid in 280 ml toluene wasrefluxed for three hours using a water separator. The mixture wasallowed to cool to room temperature prior to the addition of 100 mlmethanol. During 30 minutes, a total of 4.0 g sodium borohydride wasadded in small portions to the stirred mixture. After stirring themixture for one hour at room temperature, 100 ml of water and 200 ml ofethylacetate was added. The organic layer was separated, the solventremoved and the residue subjected to conventional work-up. Thereby, thefree base(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olwas obtained.

In order to prepare the corresponding hydrochloride, the product wasdissolved in 100 ml ethanol and treated with 14,27 ml of a 1N solutionof hydrochloric acid in water. The solvents were removed and the residuerecrystallized from 50 ml of ethanol. Thereby, the compound(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olwas obtained as monohydrochloride-hemihydrate in enantiomerically pureform.

Example 5

The affinity to the 5-HT_(1A) receptor can be determined in vitro byradioligand binding experiments according to Cossery J M et al. (Eur. J.Pharmacol. 1987; 140: 143-155). The functional agonistic properties atthe 5HT_(1A) receptor can be determined in vitro in the GTP-gamma-S test(Newman-Tancredi A et al., Eur. J. Pharmacol.1996; 307: 107-111). Astandard in vivo animal model to test for the 5HT_(1A) agonisticproperties is the ultrasonic vocalization test in rats (e.g. deFry J etal., Eur. J. Pharmacol. 1993; 249: 331-339; Sanchez C, Behav. Pharmacol.1993; 4: 269-277). The affinity for dopamine D4 receptors can bedetermined in vitro by radioligand binding experiments according toKlokow M et al. (Drug Res. 1986; 36: 197-200). Compound(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olbinds to 5HT_(1A) receptors with an IC₅₀ value of 10 nM and to D4receptors with an IC₅₀ of 12 nM. Furthermore, it has no or only a veryweak binding to D2 receptors. Its 5HT_(1A) agonistic properties areconfirmed in vitro in the GTP-gamma-S test with an ED₅₀ of 33 nM and invivo in the ultrasonic vocalization test with an ED₅₀ of 2 mg/kg.

The examples which follow relate to pharmaceutical products:

Example A Vials

A solution of 100 g of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt or solvate thereof and 5 g ofdisodium hydrogen phosphate in 3 l of twice-distilled water is broughtto pH 6.5 with 2N hydrochloric acid, filter-sterilized, filled intovials, lyophilized under sterile conditions and sealed in sterile form.Each vial comprises 5 mg of active ingredient.

Example B Suppositories

A mixture of 20 g of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt or solvate thereof is melted with100 g of soya lecithin and 1400 g of cocoa butter, and the mixture ispoured into moulds and left to cool. Each suppository comprises 20 mg ofactive ingredient.

Example C Solution

A solution is prepared from 1 g of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt or solvate thereof, 9.38 g ofNaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g of benzalkoniumchloride in 940 ml of twice-distilled water. The pH is brought to 6.8,and the solution is made up to 1 l and sterilized by irradiation. Thissolution can be used in the form of eyedrops.

Example D Ointment

500 mg of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt or solvate thereof are mixed with99.5 g of petroleum jelly under aseptic conditions.

Example E-1 Tablets

A mixture of 1 kg of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt or solvate thereof, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is tableted in the customary manner in such a way that eachtablet comprises 10 mg of active ingredient.

Example E-2 Tablets

A mixture of 20 g of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate, 1 kg of l-dopa, 250 g benserazide, 4 kgof lactose, 1.6 kg of potato starch, 0.2 kg of talc and 0.1 kg ofmagnesium stearate is tableted in the customary manner in such a waythat each tablet comprises 0,2 mg(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olmonohydrochloride hemihydrate, 10 mg of l-dopa and 2,5 mg benserazide.

Example F Sugar-Coated Tablets

A mixture is tableted analogously to Example E, and the tablets aresubsequently coated in the customary manner with a coating of sucrose,potato starch, talc, tragacanth and colouring.

Example G Capsules

2 kg of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt or solvate thereof are filled intohard gelatin capsules in the customary manner to that each capsulecomprises 20 mg of the active ingredient.

Example H Ampoules

A solution of 1 kg of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt or solvate thereof in 60 l oftwice-distilled water is filter-sterilized, filled into ampoules,lyophilized under sterile conditions and sealed in sterile form. Eachampoule comprises 10 mg of active ingredient.

Example I Spray for Inhalation

14 g of(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-olor a physiologically acceptable salt or solvate thereof are dissolved in10 l of isotonic NaCl solution, and the solution is filled intocommercially available pump-operated spray containers. The solution canbe sprayed into mouth or nose. One actuation (approximately 0.1 ml)corresponds to a dose of approximately 0.14 mg.

1. A pharmaceutical composition comprising a pharmaceutically acceptablesalt of a compound of formula IA

wherein said salt is formed from an acid selected from the groupconsisting of hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methanesulphonic acid, ethanesulphonic acid,toluenesulphonic acid, benzenesulphonic acid, naphthalene acid,disulphonic acid, acetic acid, propionic acid, lactic acid, tartaricacid, citric acid, fumaric acid, maleic acid and benzoic acid, includingoptical isomers thereof, and which A) is in the form of a tablet, pill,sugar-coated tablet, capsule, suppository transdermal plaster, ointment,cream or lyophilisate, and which comprises a solid, liquid or semiliquidexcipient or adjunct; or B) 1) comprises a solid, liquid or semiliquidexcipient or adjunct which is not water, or 2) comprises a vegetableoil, benzyl alcohol, alkylene glycol, polyethylene glycol, glyceroltriacetate, gelatine, carbohydrate lactose, starch, magnesium stearate,talc, or petroleum jelly.
 2. A pharmaceutical composition according toclaim 1, which contains a pharmaceutically acceptable saltof(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin3ylmethyl]-amino}-methyl)-chroman-4-ol.
 3. A pharmaceutical compositionaccording to claim 1, further comprising at least one anti-Parkinsoniandrug.
 4. A pharmaceutical composition according to claim 3, wherein saidanti-Parkinsonian drug is l-dopa.
 5. A pharmaceutical compositionaccording to claim 2, which contains the monohydrochloride hemihydrateof(2R,4R)-2({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol.6. A pharmaceutical composition according to claim 1, which contains themonohydrochloride hemihydrateof(2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol.7. A pharmaceutical composition according to claim 1, which comprises atleast one solid, liquid or semiliquid excipient or adjunct, which is notwater.
 8. A pharmaceutical composition according to claim 2, whichcompromises at least one solid, liquid or semiliquid excipient oradjunct, which is not water.
 9. A pharmaceutical composition comprisingcompound of formula IA

or a pharmaceutically acceptable salt of a compound of formula IA,including optical isomers thereof, wherein said pharmaceuticallyacceptable salt is formed from an acid selected from hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonicacid, ethanesulphonic acid, toluene sulphonic acid, benzenesulphonicacid, naphthalene-disulphonic acid, acetic acid, propionic acid, lacticacid, tartaric acid, citric acid, fumaric acid, maleic acid, and benzoicacid, including optical isomers thereof, and which A) is in the form ofa tablet, pill, sugar-coated tablet, capsule, suppository transdermalplaster, ointment, cream or lyophilisate, and which comprises a solid,liquid or semiliquid excipient or adjunct: or B) 1) comprises a solid,liquid or semiliquid excipient or adjunct which is not water, or 2)comprises a vegetable oil, benzyl alcohol, alkylene glycol, polyethyleneglycol, glycerol triacetate, gelatine, carbohydrate lactose, starch,magnesium stearate, talc, or petroleum jelly.
 10. A pharmaceuticalcomposition according to claim 9, which comprises(2R,4R)-2-({[5-(4fluorophenyl)-pyridin-3ylmethyl]-amino}-methyl)-chroman-4-ol,or a pharmaceutically acceptable salt of it.
 11. A pharmaceuticalcomposition according to claim 1, which is in the form of a tablet,pill, sugar-coated tablet, capsule, suppository, transdermal plaster,ointment, cream or lyophilisate, and which comprises a solid, liquid orsemiliquid excipient or adjunct.
 12. A pharmaceutical compositionaccording to claim 2, which is in the form of a tablet, pill,sugar-coated tablet, capsule, suppository, transdermal plaster,ointment, cream or lyophilisate, and which comprises a solid, liquid orsemiliquid excipient or adjunct.
 13. A pharmaceutical compositionaccording to claim 1, which comprises a vegetable oil, benzyl alcohol,alkylene glycol, polyethylene glycol, glycerol triacetate, gelatine,carbohydrate, lactose, starch, magnesium stearate, talc, or petroleumjelly.
 14. A pharmaceutical composition according to claim 2, whichcomprises a vegetable oil, benzyl alcohol, alkylene glycol, polyethyleneglycol, glycerol triacetate, gelatine, carbohydrate, lactose, starch,magnesium stearate, talc, or petroleum jelly.
 15. A pharmaceuticalcomposition according to claim 9, which comprises at least one solid,liquid or semiliquid excipient or adjunct, which is not water.
 16. Apharmaceutical composition according to claim 10, which comprises atleast one solid, liquid or semiliquid excipient or adjunct, which is notwater.
 17. A pharmaceutical composition according to claim 9, which isin the form of a tablet, pill, sugar-coated tablet, capsule,suppository, transdermal plaster, ointment, cream or lyophilisate, andwhich comprises a solid, liquid or semiliquid excipient or adjunct. 18.A pharmaceutical composition according to claim 10, which is in the formof a tablet, pill, sugar-coated tablet, capsule, suppository,transdermal plaster, ointment, cream or lyophilisate, and whichcomprises a solid, liquid or semiliquid excipient or adjunct.
 19. Apharmaceutical composition according to claim 9, which comprises avegetable oil, benzyl alcohol, alkylene glycol, polyethylene glycol,glycerol triacetate, gelatine, carbohydrate, lactose, starch, magnesiumstearate, talc, or petroleum jelly.
 20. A pharmaceutical compositionaccording to claim 10, which comprises a vegetable oil, benzyl alcohol,alkylene glycol, polyethylene glycol, glycerol triacetate, gelatine,carbohydrate, lactose, starch, magnesium stearate, talc, or petroleumjelly.